A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy
| Autor: | Marla L. Watt, Sarah Jinn, Nathan G. Hatcher, Lei Ma, Mali Cosden, Monika Kandebo, Christine Burlein, Christina Minnick, Mark E. Fraley, Cheryl A. Gretzula, Wei Lemaire, Rose B. Flick, Sean M. Smith, James Mulhearn, Gregory C. Adam, Jacob Marcus, Robert E. Drolet, Dawn Toolan, Lihang Yao |
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| Rok vydání: | 2021 |
| Předmět: |
Glucocerebrosidase
Pathology medicine.medical_specialty Synucleinopathies Lysosomal biology Parkinson's disease Preformed fibril model Primary Cell Culture Neurosciences. Biological psychiatry. Neuropsychiatry In Vitro Techniques medicine.disease_cause Glycosphingolipids Mice Protein Aggregates chemistry.chemical_compound Lysosome medicine Animals Glucosylceramide synthase inhibitor Neurons Alpha-synuclein Benzoxazoles Mutation Chemistry Dopaminergic Neurons Neurodegeneration Parkinson Disease Biological activity Glycosphingolipid medicine.disease Rats carbohydrates (lipids) medicine.anatomical_structure Neurology Glucosyltransferases alpha-Synuclein Glucosylceramidase lipids (amino acids peptides and proteins) Neuron Lysosomes RC321-571 |
| Zdroj: | Neurobiology of Disease, Vol 159, Iss, Pp 105507-(2021) |
| ISSN: | 0969-9961 |
| Popis: | Mutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids may contribute to the underlying pathology of PD, possibly via altering lysosomal function. While reduction of GCase activity exacerbates α-synuclein (α-syn) aggregation, it has not been determined that this effect is the result of altered glycosphingolipid levels and lysosome function or some other effect of altering GCase. The glycosphingolipid GlcCer is synthesized by a single enzyme, glucosylceramide synthase (GCS), and small molecule inhibitors (GCSi) reduce cellular glycosphingolipid levels. In the present studies, we utilize a preformed fibril (PFF) rodent primary neuron in vitro model of α-syn pathology to investigate the relationship between glycosphingolipid levels, α-syn pathology, and lysosomal function. In primary cultures, pharmacological inhibition of GCase and D409V GBA1 mutation enhanced accumulation of glycosphingolipids and insoluble phosphorylated α-syn. Administration of a novel small molecule GCSi, benzoxazole 1 (BZ1), significantly decreased glycosphingolipid concentrations in rodent primary neurons and reduced α-syn pathology. BZ1 rescued lysosomal deficits associated with the D409V GBA1 mutation and α-syn PFF administration, and attenuated α-syn induced neurodegeneration of dopamine neurons. In vivo studies revealed BZ1 had pharmacological activity and reduced glycosphingolipids in the mouse brain to a similar extent observed in neuronal cultures. These data support the hypothesis that reduction of glycosphingolipids through GCS inhibition may impact progression of synucleinopathy and BZ1 is useful tool to further examine this important biology. |
| Databáze: | OpenAIRE |
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